This Program Project consists of four integrated projects that explore the mechanisms, functional consequences, and prevention of cochlear damage/hearing loss induced by ototoxic drugs and acoustic over- stimulation. In addition to its basic scientific merit, the project has clinical implications with regard to acquired hearing loss (HL) in humans. The clinical motivations for Projects 1 and 2 are (a) a growing awareness that inner hair cell (IHC) loss may underlie many of the perceptual difficulties experienced by people with acquired HL, and (b) a lack of clinical tools for assessing IHC loss. Clinical motivations for Projects 3 and 4 include observations that (a) susceptibility to HL varies tremendously among individuals, and (b) identification of the factors that contribute to susceptibility may be crucial for preventing acquired HL in the future. All four projects utilize the chinchilla, a mammal whose hearing capabilities are similar to humans. Project 1 examines anatomical, physiological, and behavioral changes associated with selected IHC lesions produced by carboplatin, an anti-cancer drug. Project 2 uses auditory evoked potentials to examine functional changes along the auditory neuroaxis associated with permanent IHC loss from carboplatin and transient cochlear deafferentation by kainic acid, a glutamate analog. Project 3 explores acoustic and biochemical methods of protecting the cochlea from hearing loss induced by acoustic over-stimulation and carboplatin. Project 4 focuses on potential protective effects on lateral and medial olivocochlear efferent fibers on hair cell loss and hearing loss induced by carboplatin, aminoglycosides, kainic acid and acoustic over-stimulation. Overlapping themes among the projects include consequences of IHC loss, central nervous system reorganization, mechanisms of ototoxic damage, and strategies for protecting the inner ear from damage.